With regard to pharmaceutical preparations useful for sustained release of drugs, many studies have been conducted for microparticles such as microspheres and nanospheres using biodegradable polymers. Various methods have been known as a process for producing such microparticles and one of them is a solvent-evaporation microencapsulation method.
As shown in Journal of Controlled Release, 2, 343-352, 1985, the solvent-evaporation microencapsulation method is a method for producing microparticles where a drug and a polymer which is a material for microparticles are dissolved in a volatile organic solvent and added to an aqueous phase to prepare an o/w type emulsion and the organic solvent is evaporated whereupon microparticles are produced. As to the solvent to be used in a solvent-evaporation microencapsulation method, it is preferred to be volatile and immiscible with water and halogenated hydrocarbons such as dichloromethane and chloroform have been widely used.
A process for producing microparticles where no halogenated hydrocarbon solvent is used has been known as well. In JP-T-9-505308, a process for producing microparticles using a mixed solvent comprising at least two among ester, alcohol and ketone is disclosed and, as examples of preferred solvents, ethyl acetate, benzyl alcohol, methyl ethyl ketone, etc. are listed. In the Examples therein, an example for producing microparticles using a mixed solvent of ethyl acetate and benzyl alcohol is mentioned.
However, halogenated hydrocarbon is an excellent solvent in view of volatility, property of formation of emulsion and solubility for biopolymers and, therefore, it is desirable to use a solvent of a halogenated hydrocarbon type for the production of microparticles.
Incidentally, when solubility of a drug in a halogenated hydrocarbon solvent is low, it is to be produced by dispersing the drug in the halogenated hydrocarbon solvent, but, in such a process, although the drug content incorporated in the microparticles becomes high, the drug is present concentratedly around the outer side of the microparticles whereby there is a problem of an excessive release in the initial stage of the release (initial burst).
Under such circumstances, in order to increase the solubility of a drug in an oily phase, it has been known to add a water-miscible solvent such as methanol or acetonitrile to a halogenated hydrocarbon (refer to JP-A-4-46115). However, in such a process, although a drug is able to be dissolved in the solvent, it is still impossible to give sufficient drug content and an initial burst is also noted. The causes therefor are that, since a solvent such as methanol or acetonitrile is miscible with water, leakage of the drug to the outer aqueous phase is larger during the production step, that the drug is not uniformly dispersed in the resulting microparticles and that the resulting microparticles are porous.